Several proteinuria-reducing targeted therapies are approved by the US Food and Drug Administration (FDA) for patients with IgA nephropathy (IgAN). In this Expert Roundtables discussion, our featured experts review these therapies and their mechanisms of action, along with promising investigational agents.

The movement to targeted therapies for IgAN is satisfying, and I think that we have much more hope that we will be able to impact this disease in the future with these agents. There are 3 recently FDA-approved agents for IgAN that are far more targeted than systemic steroids: the targeted-release formulation of budesonide and the dual endothelin angiotensin receptor antagonist (DEARA) sparsentan, both of which have full FDA approval, and the CFB inhibitor iptacopan, which was granted accelerated approval. It is an exciting time now that we have these new agents that we can use to try to decrease inflammation.

Interestingly, although complement is not one of the “4 hits” of IgAN pathogenesis, 1 of those hits is immune complex formation, and another is the deposition of those immune complexes onto the mesangium of the kidney. Once immune complexes are deposited, they very well could be activating the complement system.

In the trial that led to FDA accelerated approval for iptacopan in the IgAN setting (ie, the APPLAUSE-IgAN study), inhibiting the complement system resulted in clinical benefit to patients. The complement system is a very unique target for us in the glomerular disease world, and I think that it holds a lot of promise for IgAN.

We treat IgAN using a patient-specific approach. If a patient has any degree of chronic kidney disease with ongoing proteinuria, particularly if they have a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m², we really want to be very solid with our chronic kidney disease management. This includes well-controlled blood pressure, diet and exercise changes, obesity management, and avoidance of smoking. Additionally, we use the maximum-tolerated dose of RAAS inhibitors, potentially combining them with SGLT2 inhibitors, and strongly consider ERAs. We want to do everything to keep the kidneys from sustaining more nonspecific injury, but targeting disease-specific, IgA-induced inflammation is also really important.

The antiproteinuric effects of sparsentan and the targeted-release formulation of budesonide are similar, and both can preserve kidney function. Because sparsentan lowers blood pressure, patients whose blood pressure is already really low are not good candidates. If someone is having severe edema, endothelin blockade may not be the ideal choice. The targeted-release formulation of budesonide can also cause mild, reversible, steroid-induced issues. Further, iptacopan can also lower proteinuria effectively, but we need to see more data about its tolerability when given long-term. So, it may be more the side effects that differentiate the newer agents than the efficacy.

The availability of these new targeted agents is a paradigm change. Although the goals of traditional therapy certainly were to preserve the kidney structure and function, with the new tools and approaches, we think that we can achieve this even better and more regularly.

When you can block 2 pathways with 1 drug, such as with sparsentan, you get a superior effect in not only reducing proteinuria but also flattening the estimated GFR slope. Over time, that will hopefully lead to fewer patients developing chronic kidney disease and end-stage kidney disease.

I think that the most interesting group of therapies for IgAN are B-cell–targeted therapies. Targeting B-cell survival factors (eg, BLyS/BAFF and APRIL) has shown great promise preclinically and in phase 2 trials. Their potential effect on both the galactose-deficient IgA and the complexing antibody (ie, the effect on both hits 1 and 2 of the underlying pathomechanism) makes them very appealing agents. The APRIL inhibitors zigakibart and sibeprenlimab and the dual-target therapies telitacicept and atacicept that target both BLyS and APRIL are now being tested in phase 3 trials. This research will hopefully increase the number of therapies that are available to treat patients with IgAN. We are in a time of plenty, but we hope that these investigational therapies might allow us to offer our young patients a more meaningful benefit without too many side effects.